DIABETES MELLITUS

Prof. ADEL A EL-SAYED MDChairman Elect

Middle East and North Africa (MENA) Region

International Diabetes Federation (IDF)

Professor of Internal Medicine

Sohag Faculty of Medicine

Sohag-EGYPT

The Problem

• Diabetes occurs world-wide and the incidence of both type 1 and type 2 diabetes are rising; it is estimated that, in the year 2000, 171 million people had diabetes, and this is expected to double by 2030.

• This global pandemic principally involves type 2 diabetes, to which several factors contribute, including greater longevity, obesity, unsatisfactory diet, sedentary lifestyle and increasing urbanizations.

3

Diabetes: the growing global burden

1Adapted from IDF. E-Atlas. Available at: www.eatlas.idf.org (accessed 26.12.08).2Diabetes Atlas, third edition© International Diabetes Federation, 2006.

International Diabetes Federation (IDF):2 • Diabetes currently affects nearly 250 million people worldwide• It is expected to affect 380 million by 2025

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2–5%

5–8%

8–11%

11–14%

14–17%

> 17%

20002000Prevalence estimates of diabetes mellitusPrevalence estimates of diabetes mellitus 20012001

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2–5%

5–8%

8–11%

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14–17%

> 17%

Prevalence estimates of diabetes mellitus 2003200320032003

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< 2%

2–5%

5–8%

8–11%

11–14%

14–17%

> 17%

Prevalence estimates of diabetes mellitus 2025202520252025

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2–5%

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1

The IDF Diabetes Atlas5th Edition

December 2011

A summary of the figures and key findings

The global burden 366 million people have diabetes in 2011; by 2030 this will have risen to

552 million

The number of people with type 2 diabetes is increasing in every country

80% of people with diabetes live in low-and middle-income countries

The greatest number of people with diabetes are between 40 to 59 years of

age

183 million people (50%) with diabetes are undiagnosed

Diabetes caused 4.6 million deaths in 2011

Diabetes caused at least USD 465 billion dollars in healthcare expenditures

in 2011; 11% of total healthcare expenditures in adults (20-79 years)

78,000 children develop type 1 diabetes every year

The Top 10s (number of people with diabetes)

The Top 10s (prevalence %)

Undiagnosed diabetes

Healthcare expenditures

• USD 465 billion spent on healthcare for diabetes

• 11% of all healthcare spending is for diabetes

• USD 1,274 is spent on diabetes care per person with diabetes in 2011

Diabetes and Tuberculosis

• Focused on the linkages between the two diseases and a review of the evidence

• Calculated the attributable cases of tuberculosis to diabetes

• Highlights areas where there is a high double burden

Key Messages

1. Diabetes is a huge and growing problem, and the costs to society are high and escalating

2. Diabetes is a neglected development issue, affecting all countries

3. There are cost-effective solutions to reverse the global diabetes epidemic

4. Diabetes is not only a health issue, its causes are multi-sectoral and it requires a multi-sectoral response

5. The UN High-level Meeting is not the end of international commitments on diabetes; it is the start of concerted and coordinated action

AETIOLOGICAL CLASSIFICATION OF DIABETES MELLITUS

• Type 1 diabetes

• Type 2 diabetes

• Gestational diabetes

• Other forms endocrine diseases such as acromegaly or Cushing's syndrome unusual genetic diseases

AETIOLOGY AND PATHOGENESIS OF DIABETES

• In both of the common types of diabetes, environmental factors interact with genetic susceptibility to determine which people develop the clinical syndrome.

• However, the underlying genes, precipitating environmental factors and pathophysiology differ substantially between type 1 and type 2 diabetes.

• Type 1 diabetes (previously IDDM) is invariably associated with profound insulin deficiency requiring replacement therapy.

• Type 2 diabetes (previously NIDDM) patients retain the capacity to secrete some insulin but exhibit impaired sensitivity to insulin (insulin resistance) and can usually be treated without insulin replacement therapy.

TYPE 1 DIABETESPathology

Type 1 diabetes is a slowly progressive T cell-mediated autoimmune disease. Family studies have produced evidence that destruction of the insulin-secreting cells in the pancreatic islets takes place over many years. Hyperglycaemia accompanied by the classical symptoms of diabetes occurs only when 70-90% of ß cells have been destroyed.

The pathological picture in the pre-diabetic pancreas in type 1 diabetes is characterised by: 'insulitis'

Islet cell antibodies can be detected before the clinical development of type 1 diabetes

Type 1 diabetes is associated with other autoimmune disorders, including thyroid disease, coeliac disease, Addison's disease, pernicious anaemia and vitiligo.

Environmental factors

• Although genetic susceptibility appears to be a prerequisite for the development of type 1 diabetes, the concordance rate between monozygotic twins is less than 40%and environmental factors have an important role in promoting clinical expression of the disease.

• The evidence that viral infection might cause some forms

of type 1 diabetes is derived from studies where virus particles known to cause cytopathic or autoimmune damage to ß cells have been isolated from the pancreas.

• Several viruses have been implicated, including mumps,

Coxsackie B4, retroviruses, rubella (in utero), cytomegalovirus and Epstein-Barr virus.

Environmental factors

• Circumstantial evidence supports the proposition that dietary factors may influence the development of type 1 diabetes.

• Bovine serum albumin (BSA), a major constituent of cow's milk, has been implicated in triggering type 1 diabetes, since children who are given cow's milk early in infancy are more likely to develop type 1 diabetes than those who are breastfed.

• Other factors.

Metabolic disturbances in type 1 diabetes

• Profound insulin deficiency is associated with metabolic sequelae.

• Hyperglycaemia leads to glycosuria and dehydration.

• Unrestrained lipolysis and proteolysis result in weight loss, increased gluconeogenesis and ketogenesis.

• When generation of ketone bodies exceeds the capacity for their metabolism, ketoacidosis results.

TYPE 2 DIABETESPathology

• Type 2 diabetes is a more complex condition than type 1 diabetes because there is a combination of resistance to the actions of insulin in liver and muscle together with impaired pancreatic ß-cell function leading to 'relative' insulin deficiency

• Insulin resistance appears to come first, and leads to elevated insulin secretion in order to maintain normal blood glucose levels.

• However, in susceptible individuals the pancreatic ß cells are unable to sustain the increased demand for insulin and a slowly progressive insulin deficiency develops.

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Adapted from DeFronzo RA. Med Clin N Am 2004;88:787–835.

Type 2 diabetes is a progressive disease: early intervention is critical

Prevention Treatment

–10 10+ YearsDiagnosis

Macrovascular complicationsMacrovascular complications

Microvascular complicationsMicrovascular complications

0

IFG/IGT Type 2 diabetes

Blood glucose

-cell function

Insulin resistance

IFG: impaired fasting glucoseIGT: impaired glucose tolerance

UKPDS: progressive decline of -cell function over time

P < 0.0001

HOMA model, diet-treated (n = 376)

Time from diagnosis (years)

100

-ce

ll f

un

ctio

n (

%) 80

60

40

20

0

Start of treatment

Adapted from Holman RR. Diabetes Res Clin Pract 1998; 40 (Suppl.):S21–S25.

–10 –9 –8 –7 –6 –5 –4 –3 –2 –1 1 2 3 4 5 6

Metabolic disturbances in type 2 diabetes

• Patients with type 2 diabetes have a slow onset of 'relative' insulin deficiency.

• Ketoacidosis are rare. • Glycosuria occurs when the blood glucose

concentration exceeds the renal threshold.• The severity of the classical 'osmotic' symptoms

of polyuria and polydipsia is related to the degree of glycosuria.

• Thus, patients are often asymptomatic, but usually present with a long history (typically many months) of fatigue, with or without osmotic symptoms.

INVESTIGATIONS

• URINE TESTING: Glucose, Ketones Protein.

• BLOOD TESTING: Glucose, Glycated haemoglobin, Blood lipids.

• The diagnostic criteria for diabetes mellitus

Clinical assessment

• Hyperglycaemia causes a wide variety of symptoms.

• The classical symptoms of thirst, polyuria, nocturia and rapid weight loss are prominent in type 1 diabetes, but are often mild or absent in patients with type 2 diabetes.

• fatigue and malaise. • increased susceptibility to infection.

Clinical assessment

• The physical signs in patients with type 2 diabetes at diagnosis depend on the mode of presentation:

• More than 70% are overweight, and obesity may be central (truncal or abdominal).

• Hypertension is present in at least 50% of patients with type 2 diabetes.

• Although hyperlipidaemia is also common, skin lesions such as xanthelasma and eruptive xanthomas are rare.

Patient Education

• Outpatient education: achieved by a multidisciplinary team (doctor, dietitian, specialist nurse and podiatris).

• Inpatient education: when insulin injections are needed.

• Self-assessment of glycaemic control: urine, SMBG.

• Education of treatment targets: BG, BP, Serum lipids.

Advice to patients with IGT

• Lifestyle advice.

• Monitoring of blood glucose level.

• Other cardiovascular risk factors should be treated aggressively.

Management

• dietary/lifestyle modification (diet and excercise).

• oral anti-diabetic agents. • insulin injections. • In parallel with treatment of

hyperglycaemia, other risk factors for complications of diabetes need to be addressed (hypertension, dyslipidaemia and advice on smoking cessation).

ORAL ANTI-DIABETIC DRUGS

• Although their mechanisms of action are different, most depend upon a supply of endogenous insulin. No role in treatment of type 1 DM.

• The sulphonylureas and the biguanides have been the mainstay of treatment for many years and have the strongest evidence of preventing complications of diabetes.

• Newer agents include the insulin sensitizers the thiazolidinediones, the a-glucosidase inhibitors and incretins.

• Primary and secondary failure.

SULPHONYLUREAS

• Mechanism of action: The principal effect of sulphonylureas is to stimulate the release of insulin from the pancreatic ß cell (insulin secretagogue).

• Indications for use: valuable in the treatment of non-obese patients with type 2 diabetes who fail to respond to dietary measures alone.

• The main differences between the individual compounds lie in their potency, duration of action and cost.

• Tolbutamide and chlorpropamide are now rarely used. • gliclazide and glipizide, glibenclamide and glimepride are

used more often now.• Side effects.

BIGUANIDES

• Metformin is the only biguanide available.

• Indications for use.

• Advantages.

• Side effects and contraindications.

• Dose and method of administration.

ALPHA-GLUCOSIDASE INHIBITORS

• The a-glucosidase inhibitors delay carbohydrate absorption in the gut.

• Acarbose or miglitol is available and is taken with each meal.

• Lower post-prandial blood glucose and modestly improve overall glycaemic control.

• The main side-effects are flatulence, abdominal bloating and diarrhoea.

THIAZOLIDINEDIONES

• These drugs (also called TZD drugs, 'glitazones' or PPAR? agonists) bind and activate peroxisome proliferator-activated receptor.

• A nuclear receptor present mainly in adipose tissue that regulates the expression of several genes involved in metabolism, and work by enhancing the actions of endogenous insulin.

• Plasma insulin concentrations are not increased and hypoglycaemia is not a problem.

• Types, price, indications, and side effects.

INCRETIN MIMETICS

• A new class of therapeutic agents is being developed for treatment of type 2 diabetes.

• The secretion of insulin in response to a rise in blood glucose is greater when glucose is given by mouth, rather than by intravenous infusion.

• In part this is caused by secretion of gut hormones, or incretins, which potentiate glucose-induced insulin secretion.

• Glucagon-like peptide (GLP-1) is an incretin hormone which stimulates insulin secretion in a glucose-dependent manner, thus hypoglycaemia is unlikely.

INCRETIN MIMETICS

• In addition, GLP-1 suppresses glucagon secretion, delays gastric emptying, reduces appetite and encourages weight loss.

• It has to be given by injection. • As GLP-1 is rapidly degraded by the enzyme,

dipeptidyl peptidase IV, inhibitors of this enzyme will have to be given to prolong its biological effect.

• Alternatively, long-acting GLP-1 analogues are being developed. These include liraglutide and exenatide (synthetic exendin-4).

• DPP4 inhibitors.

INSULIN

• History, manufacture and formulation.• Regular insulin.• The duration of action of short-acting,

unmodified insulin ('soluble' or 'regular' insulin), which is a clear solution, can be extended by the addition of protamine and zinc at neutral pH (isophane or NPH insulin) or excess zinc ions (lente insulins).

• Pre-mixed formulations.• Insulin analogues.

INSULIN

• Insulin delivery.

• Insulin regimens.